Process for the preparation of macrocyclic chelants and the chelates thereof with paramagnetic metal ions

ABSTRACT

A process for the preparation of complexes of macrocyclic chelants with paramagnetic metal trivalent ions of formula (XII) ##STR1## wherein R 1 , R 2  and Me 3+  are as described in the following, comprising: a) reaction of 1,4,7,10-tetraazacyclododecane with triethyl orthoformate to give 5H,9bH-2a,4a,7,9a-octahydrotetraazacycloocta cd!pentalene; b) carboxymethylation reaction in water; c) hydrolysis reaction in basic conditions; d) alkylation according to known methods with an epoxide in water; e) complexation according to known methods carried out in water by addition of a paramagnetic metal salt; f) purification by diafiltration, final desalting of the aqueous solution on ion exchange resins and g) crystallization or recovery.

The present invention relates to a process for the preparation ofmacrocyclic chelates with paramagnetic metal ions of formula (XII)##STR2## wherein R₁ and R₂ are independently a hydrogen atom, a (C₁-C₂₀) alkyl containing 1 to 10 oxygen atoms, or a phenyl, phenyloxy,phenyldioxy group, which can be unsubstituted or substituted with a (C₁-C₅) alkyl or hydroxy, (C₁ -C₅) alkoxy, carbamoyl or carboxylic groups;

Me³⁺ is the trivalent ion of a paramagnetic metal.

This type of complexes with metal ions, in particular with paramagneticmetal ions, is used for the preparation of non-ionic contrast agents forthe diagnostic technique known as magnetic resonance (MRI, MagneticResonance Imaging), among which are ProHance® (Gadoteridol, gadoliniumcomplex of10-(2-hydroxy-propyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triaceticacid), and Gadobutrol (gadolinium complex of 10-2,3-dihydroxy-1-(hydroxymethyl)propyl!-1,4,7,10-tetraazacy-clododecane-1,4,7-triaceticacid). ##STR3##

Two different synthetic approaches are described in literature for thepreparation of this kind of complex, the approaches differing in thestrategy taken to discriminate one of the four nitrogen atoms: the firstone (Dischino et al., Inorg. Chem., 1991, 30, 1265 or EP 448191, EP292689, EP 255471) is based on the selective protection of one of thenitrogen atoms by formation of the compound of formula (III),5H,9bH-2a,4a,7-tetraazacycloocta cd!pentalene, and on the subsequenthydrolysis to the compound of formula (IV),1-formyl-1,4,7,10-tetraazacyclododecane, followed by thecarboxymethylation of the still free nitrogen atoms and by thedeprotection and alkylation of the fourth nitrogen atom, according toscheme 1. ##STR4##

The step from 1,4,7,10-tetraazacyclododecane disulfate (a commerciallyavailable product) to compound (III) is effected according to theconventional method disclosed in U.S. Pat. No. 4,085,106, followed byformation of the compound of formula (IV) in water-alcohol medium.

This intermediate is subsequently tricarboxymethylated with tert-butylbromoacetate (TBBA) in dimethylformamide at 2.5° C. and then treatedwith a toluene-sodium hydroxide diphasic mixture to give the compound offormula (V), 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic,tris(1,1-dimethylethyl) ester, which is subsequently hydrolysed tocompound of formula (II) in acidic solution.

In the process described in WO 93/24469 for the synthesis of Gadobutrol,at first one of the nitrogen atoms is alkylated in conditions such as tominimize the formation of polyalkylated derivatives, then themonoalkylderivative is purified and carboxymethylated, according toscheme 2. ##STR5##

The alkylation of 1,4,7,1,0-tetraazacyclododecane with the epoxide offormula (VI), 4,4-dimethyl-3,5,8-trioxabicyclo 5.1.0!octane, is carriedout in anhydrous n-BuOH under reflux and the reaction mixture isextracted with water, evaporated to dryness and the residue issubsequently diluted with water and extracted with methylene chloride.

The aqueous phase containing the mono-alkylated product (65% yield inExample 7 which reports the procedure for the preparation of 5 kg ofGadobutrol) is directly carboxymethylated at 70° C. with chloroaceticacid, keeping pH 9.5 by addition of NaOH. The reaction mixture isadjusted to pH 1, concentrated to dryness and dissolved in methanol toremove the undissolved salts. The filtrate is then concentrated undervacuum, dissolved in water, and loaded onto a cation exchanger in the H⁺form to fix the product. The subsequent elution with ammonia displacesthe desired product, which is concentrated to small volume andsubsequently complexed with gadolinium oxide according to conventionalmethods, and the resulting complex is purified by means of ion exchangeresins. The overall yield is 42%.

Although the first of these two processes could theoretically provide ahigher yield, in that all the individual steps (protection,carboxymethylation and deprotection) are highly selective, thecomplexity of the operations required to remove salts and solvents andto purify the reaction intermediates makes such theoretical advantageineffective: the overall yield is in fact, in the case of Gadoteridol,slightly higher than 37%.

The preparation of Gadobutrol according to the alternative process (WO93/24469) provides a markedly better yield (72%) only on a laboratoryscale (example 2): example 7 (represented in the above Scheme 2)actually evidences that, when scaling-up, the yield of this process alsoremarkably decreases (42%).

In addition to the drawback of an about 40% yield, both processes of theprior art are characterized by troublesome operations, which ofteninvolve the handling of solids, the use of remarkable amounts of anumber of different solvents, some of them having undesirabletoxicological or at least hazardous characteristics.

Moreover, the synthesis described by Dischino makes use of reagentswhich are extremely toxic, such as tert-butyl bromoacetate, or harmfuland dangerous from the reactivity point of view, such asdimethylformamide dimethylacetal.

It is the object of the present invention to provide a process for thepreparation of the complexes of general formula (XII) ##STR6## whereinR₁ and R₂ are independently a hydrogen atom, a (C₁ -C₂₀) alkylcontaining 1 to 10 oxygen atoms, or a phenyl, phenyloxy, phenyldioxygroup, which can be unsubstituted or substituted with a (C₁ -C₅) alkylor hydroxy, (C₁ -C₅) alkoxy, carbamoyl or carboxylic groups, Me³⁺ is thetrivalent ion of a paramagnetic metal;

comprising the steps represented in the following Scheme 3: ##STR7##wherein: a) is the formation of5H,9bH-2a,4a,7,9a-octahydro-tetraazacycloocta cd!pentalene of formula(III) starting from 1,4,7,10-tetraazacyclododecane with triethylorthoformate, in the presence of an acid catalyst;

b) is the carboxymethylation reaction of compound (III), in water, inmolar ratios ranging from 3 to 5 mol/mol of haloacetic acid to compound(III), at pH ranging from 9.5 to 12.5 by addition of an alkali oralkaline-earth metal hydroxide, at a temperature between 7 and 50° C.,for a time from 3 to 48 h, to give the intermediate salt of10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid of formula(IX) which is hydrolized in step c), without being isolated;

c) is the hydrolysis reaction of intermediate (IX), in water, in basicconditions by addition of the same base as in step b), at pH higher than12.5, at a temperature from 65° C. to 100° C. and for a time from 5 to48 h, to give an aqueous solution of the1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid salt of formula (X),which undergoes step d) without being isolated;

d) is the alkylation reaction, according to known methods, carried outin water with an epoxide of formula (XI), in which R₁ and R₂ have themeanings defined above, to give compound (I) as a salt, which undergoesstep e) without being isolated;

e) is a complexation step, according to known methods, effected in waterby addition of a salt of the paramagnetic metal trivalent ions havingatomic numbers variable from 20 to 31, 39, 42, 43, 44, 49, or from 57 to83, to give the aqueous solution of the paramagnetic complex of formula(XII), which undergoes step f) without being isolated;

f) is a purification step, consisting of: diafiltration of the aqueoussolution of compound (XII) to remove most salts and low-molecular weightimpurities, optionally preceded by a chromato-graphic purification stepto remove the lipophilic impurities; final desalting of the aqueoussolution on ion exchange resins; and

g) crystallization and recovery of compound (XII).

The process of the present invention keeps the high selectivity typicalof the protection/deprotection strategy described by Dischino in theabove mentioned paper, while removing all its drawbacks, thus providingfor the first time a reproducible industrial process for the preparationof the concerned compounds in high yields and without use of hazardoussubstances.

The preparation of the gadolinium complex of10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic)acid (Gadoteridol), according to scheme 4, is particularly preferred:##STR8## in which the synthetic steps a), b), c), d), e), and f) havethe meanings defined above and the epoxide of formula (XI) in step d) ispropylene oxide.

The preparation of the gadolinium complex of 10-2,3-dihydroxy-1-(hydroxymethyl)propyl!-1,4,7,10-tetra-azacyclododecane-1,4,7-triacetic)acid (Gadobutrol), according to the scheme 5, is also preferred.##STR9## in which the synthetic steps a), b), c), d), e), and f) havethe meanings defined above and the epoxide of formula (XI) in step d)corresponds to the one of formula (VI), defined above.

On the other hand, step a) of the process of the present inventioninvolves the use of triethyl orthoformate in the presence of an acidcatalyst, instead of dialkylformamide-dialkylacetal.

Triethyl orthoformate can be added in amounts ranging from 105% to 200%on the stoichiometric value.

The reaction temperature can range from 110 to 150° C. and the reactiontime from 5 to 24 h.

The catalyst is a carboxylic acid having at least 3 carbon atoms, C₃-C₁₈, preferably selected from the group consisting of propionic,butyric and pivalic acids.

Triethyl orthoformate is a less toxic and less expensive product thanN,N-dimethylformamide-dimethyl-acetal and does not involve the formationof harmful, not-condensable gaseous by-products. Moreover, triethylorthoformate is less reactive than theN,N-dimethyl-formamide-dimethylacetal reagent, which makes it possibleto carry out the loading procedures of the reagent as well as thereaction itself under totally safe conditions even on a large scale,allows one to better monitor the progress of the reaction on the basisof such operative parameters as time and temperature, without checkingthe progress by gas chromatography, and makes dosing the reactive lesscritical, in that it can be added from the very beginning withoutcausing the formation of undesired by-products: all that rendering theprocess suitable for the production of compound (III) on the industrialscale in easily reproducible conditions.

The subsequent step b) involves the carboxymethylation of compound (III)in aqueous solution, using a haloacetic acid, to give compound (IX),i.e. the 10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acidsalt with an alkali or alkaline-earth metal, the salts of compound (IX)with sodium, potassium or calcium being most preferred. ##STR10##

The preferred conditions to carry out step b) are the following ones:

haloacetic acid to compound (III) molar ratio from 3.2 to 4.5;

pH from 10 to 12;

the haloacetic acid is chloroacetic or bromoacetic, preferablybromoacetic, acid.

Step c) is the hydrolysis reaction of intermediate (IX) in water, inbasic conditions by addition of the same base as in step b), at pHhigher than 12.5, at a temperature from 65° C. to 100° C. and for a timefrom 5 to 48 h, to give an aqueous solution of the salt of compound (X),which undergoes step d) without being isolated.

The process of the present invention thus makes it possible to carry outthe carboxymethylation of compound (III) and the hydrolysis of compound(IX) in aqueous solution, thereby completely avoiding the use ofundesired organic solvents.

Step d) is the alkylation reaction of compound (X) according to methodsdescribed in literature.

For example, in the case of the preparation of Gadoteridol, as describedin EP 292,689, the alkaline aqueous solution of the compound (X) istreated with propylene oxide at room temperature to give, after thealkylation reaction,10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid(commonly known as HPDO3A).

The case of Gadobutrol is quite the same, except for the use of4,4-dimethyl-3,5,8-trioxabicyclo- 5.1.0!octane of formula (VI) asalkylating agent in place of propylene oxide.

Step e) is the complexation reaction, according to conventional methods,carried out in water by addition of a salt of the paramagnetic metaltrivalent ions having atomic number variable from 20 to 31, 39, 42, 43,44, 49, or from 57 to 83.

The trivalent ions of Gd, Dy, Yb metals are preferred, gadolinium beingmost preferred.

Step f) is a purification step, consisting of: diafiltration of theaqueous solution to remove most salts and low-molecular weightimpurities, optionally preceded by a chromatographic purification stepto remove the lipophilic impurities; a final desalting of the aqueoussolution on ion exchange resins; and crystallization and recovery.

The diafiltration treatment is useful to remove most salts, which arepresent in the solution from the preceding steps in remarkable amountsas by-products from the carboxymethylation and hydrolysis reactions.

Diafiltration can be carried out using commercial nanofiltrationmembranes, characterized by very high permeability to monovalent ionsbut substantially impermeable to the gadolinium complexes of generalformula (I): for example, the spiral-wound membrane elements Desal DK,Dow Chemical Filmtec NF45 and Daicel DRA can be cited.

Diafiltration can be carried out according to the teachings by Bungay P.M. et al., ("Synthetic Membranes", Science Engineering Application, D.Reidel, C181, 1986) or also in the conditions described in U.S. Pat. No.5,447,635.

The crude solution can be fed to nanofiltration through a in linefilter, for example a cartridge, to remove any gadolinium oxideparticles present, and possibly also through a column containing anabsorbing resin or a reversed-phase liquid chromatography stationaryphase, in order to remove chromatographically the more lipophilicimpurities.

In this case, the product can be eluted with water from the resin, andthe aqueous eluate can be combined with the product fraction andreconcentrated in the same nanofiltration unit.

The absorbing resin can be selected from those .commercially available:for example, R&H XAD1600 or 1600T, Bayer Lewatit OC1062 or 1064, DiaionSP800 or SP825 can be cited.

The treated solution is, as a result, concentrated and free from mostsalts, but it still contains small amounts of inorganic salts andsignificant amounts of organic ionic impurities, therefore it is fed toa ion exchange unit for the final purification from ionic impurities.

The ion exchange unit should preferably be designed so that the productis not subjected to pH values below 4, which would cause a significantloss of yield due to the dissociation of the gadolinium complex: afterdissociation into free ligand and gadolinium, both ligand and gadoliniumwould be blocked by the resin.

To avoid this drawback, desalting cannot be carried out in separate bedunits containing strongly acidic ion exchangers: it can be carried out,on the contrary, in a mixed bed unit or, better, in a separate bed unitwhich uses no strongly acidic cation exchangers: for this purpose, aunit consisting of 4 beds can be used, the first bed (C1) being astrongly basic anion exchanger in the hydrogen carbonate form, thesecond (C2) being a weakly acidic cation exchanger in the H⁺ form, thethird (C3) being a small size, strongly basic anion exchanger in the OH⁻form and the fourth (C4) being a small size, weakly acidic cationexchanger in the H⁺ form.

The strongly basic anion exchanger can be selected from a groupconsisting of any of the commercially available, gel or macroporous,type I or type II exchange resin, for example R&H Amberjet 4200 or 4400or IRA 900, Diaion Relite 3A or 3AS, Dow Chemical Dowex Monosphere AI500or AI550 or AII500.

When available, commercial grades are preferred, which are characterizedby particles conventionally defined as in small size, since they providea faster exchange: for example, in the case of the Diaion 3A or 3ASresins, the "fb" grade is preferred, and for the Dowex Monosphere AIresin the AI500 grade is preferred.

The weakly acidic cation exchanger can be selected from a groupconsisting of all the commercially available products: the gel-matrixproducts are preferred to the macroporous-matrix ones. For example,among the preferred resins, R&H IRC86, Diaion Relite CC and Dow ChemicalDowex CCR3 can be cited.

When available, commercial grades characterized by particlesconventionally defined as small size are preferred, since they provide afaster exchange: for example, in the case of the Dow Chemical Dowex CCR3resin, the "lb" grade is preferred.

The desalted solution, which usually contains only the desired productat very high purity, can then be concentrated by heating to a dryresidue or to a viscous residue and then added with a solvent, typicallya water-soluble alcohol, to precipitate the final product.

In the case of the preparation of Gadoteridol and Gadobutrol accordingto the process of the present invention, a high quality final productcan be obtained in yield equal to or higher than 80%. No traces ofimpurities can be detected in the final products.

The following examples illustrate the best experimental conditions tocarry out the process of the invention.

EXPERIMENTAL SECTION Example 1 Preparation of Gadoteridol ##STR11## A)Preparation of 5H,9bH,2a,4a,7-octahydrotetraazacy-clododecanecd!pentalene

23.8 kg (0.138 kmol) di 1,4,7,10-tetraazacyclododecane, containing 0.7%w/w of water, are dissolved in 23.8 kg of amyl alcohol. The water-amylalcohol azeotrope and the amyl alcohol excess are distilled insuccession under reduced pressure, then 24.5 kg (0.166 kmol) of triethylorthoformate and 355 g of propionic acid are added, under nitrogenatmosphere. The mixture is heated for 11 h at 125° C., while distillingthe formed ethanol, then the reaction mass is cooled to 35° C., toobtain the desired compound as a fluid oil.

B) Preparation of10-formyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodiumsalt

The compound from A) is added to a solution prepared dissolving 81.5 kg(0.469 kmol) of bromoacetic acid and about 62.6 kg of 30% w/w NaOH in100 kg of water to pH 5. During the addition of the crude compound, pHis kept at 11 by addition of NaOH; at the end of the addition pH isincreased to 11.1 again by addition of 30% w/w NaOH, and the mixture isreacted for 24 h at 35° C. at the same pH value.

C) Preparation of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acidsodium salt (DO3A)

77.3 kg of 30% w/w NaOH are added to compound from step b), heating at70° C. for 9 h. The resulting aqueous solution contains 0.131 kmol ofthe desired compound (content determined by HPLC), as the trisodiumsalt.

D) Synthesis of Gadoteridol

pH is adjusted to 12.3 with conc. HCl, 15.2 kg (0.262 kmol) of propyleneoxide are added and the mixture is reacted for 4 h at 40° C. After that,the solution is heated to 50° C. and 120 kg of an aqueous solutioncontaining 0.135 kmol of gadolinium trichloride are added. After 1 h,the reaction is cooled to 17° C. and acidified to pH 1.7 with conc. HCl,keeping this pH for 2 h. Subsequently, the solution is heated to 50° C.and pH is adjusted to 7 with sodium hydroxide, keeping these conditionsfor 1 h.

E) Prepurification of the Gadoteridol crude solution

The Gadoteridol crude solution from the previous step is cooled andtransferred to a nanofiltration unit fitted with Desal DK404OFcomponents through a in line filter and a column packed with 150 L ofR&H Amberlite XAD 1600 resin. When the reactor is empty, the reactor,the in line filter and the column are washed three times with 300 L ofdeionized water.

The resulting washing solution is combined with the product solution inthe nanofiltration unit, where the product is concentrated and partiallydesalted under 32 bar and at 25° C.

250 L of crude Gadoteridol solution with a conductivity of 2.9 mS/cm areobtained finally.

F) Final desalting

The Gadoteridol solution is then fed at 200 L/h to a series of 4 ionexchanger beds, the first (C1) consisting of 120 L of strongly basicanion exchanger Relite 3ASfb in the hydrogen carbonate form, the second(C2) consisting of 100 L of weakly acidic cation exchanger Relite CC inthe H⁺ form, the third (C3) consisting of 20 L of Relite 3ASfb in theOH⁻ form and the fourth (C4) consisting of 20 L of Relite CC resin inthe H⁺ form. All the columns are vented to the atmosphere and the liquidfrom the second column is passed through a gas separation tank,connected with a vacuum pump, to remove the evolved CO₂ from thesolution. The outlet from the fourth column is fitted with a densitytransmitter to detect the product in the eluate.

The first 180 L of eluate are discarded; the eluate is then collected ina product-rich fraction. When all the crude Gadoteridol solution hasbeen loaded onto the ion exchange unit, the product is eluted with 600 Lof deionized water, the eluate is then combined with the product-richfraction, which is colourless and substantially free from saltimpurities (conductivity 2.2 μS/cm).

The yield of the final desalting, determined on the basis of the HPLCassay, is 98%.

G) Recovery of the product (Gadoteridol)

The product-rich fraction is then thermally concentrated to a thickresidue, which is added with 350 kg of isopropanol at 79° C. Theresulting suspension is refluxed for 1 h, then cooled, centrifuged anddried under reduced pressure, to obtain 68.2 kg of Gadoteridolcontaining 10% of hydration water (0.111 kmol), HPLC assay 98.5% (s.a.).

Overall yield: 80.7%

The IR and MS spectra are consistent with the indicated structure.

Example 2 Preparation of Gadobutrol ##STR12##

The procedure of Example 1 is followed until step C included, to obtaina solution of DO3A trisodium salt.

pH is adjusted to 12.3 with conc. HCl and 57.7 kg (0.4 kmol) of4,4-dimethyl-3,5,8-trioxabicyclo 5.1.0!-octane are added. After reactionfor 4 h at 40° C. and for 8 h at 80° C., the solution is cooled to 50°C., 120 kg of an aqueous solution containing 0.135 kmol of gadoliniumtrichloride are added. After 1 h the mixture is cooled at 17° C. andacidified to pH 1.7 with conc. HCl, keeping this pH for 2 h. Thesolution is subsequently warmed to 50° C., pH is adjusted to 7 withsodium hydroxide, keeping these conditions for 1 h.

After that, the resulting crude Gadobutrol is purified repeating exactlythe same process as in steps E and F of Example 1.

Recovery of the product (Gadobutrol)

The product-rich fraction is then thermally concentrated to a viscousresidue and the residue is added with 350 kg of ethanol at 79° C.

The resulting suspension is refluxed for 1 h, then cooled, centrifugedand dried under reduced pressure to obtain 66.0 kg of Gadobutrol (0.109kmol), HPLC assay 99.5% (A%).

Overall yield: 79.1%

The IR and MS spectra are consistent with the indicated structure.

We claim:
 1. A process for the preparation of complexes of macrocyclicchelants with trivalent ions of paramagnetic metals of formula (XII)##STR13## wherein R₁ and R₂ are independently a hydrogen atom, a (C₁-C₂₀) alkyl containing 1 to 10 oxygen atoms, or a phenyl, phenyloxy,phenyldioxy group, which can be unsubstituted or substituted with a (C₁-C₅) alkyl or hydroxy, (c₁ -C₅) alkoxy, carbamoyl or carboxylic groups;Me³⁺ is the trivalent ion of a paramagnetic metal; comprising the stepsshown in the following scheme: ##STR14## a) reaction of1,4,7,10-tetraazacyclododecane with triethyl orthoformate in the absenceof solvent and in the presence of an acid catalyst, at a hightemperature, to give 5H, 9bH-2a,4a,7,9a-octahydro-tetraazacyclooctacd!pentalene of formula (III);b) carboxymethylation reaction of compound(III) in water, in basic conditions, with a haloacetic acid, to give theintermediate of formula (IX), which is subjected to the hydrolysisreaction of the subsequent step c) without being isolated; c) hydrolysisreaction of intermediate (IX) in basic conditions, by addition of thesame base as added in step b), to give an aqueous solution of the saltof formula (X), which undergoes the subsequent step d), without beingisolated, d) alkylation in water, according to known methods, with anepoxide of formula (XI), wherein R₁ and R₂ have the meanings definedabove, to give a corresponding salt of compound (I) which undergoes stepe) without being isolated; e) complexation according to known methodscarried out in water by addition of a salt of a paramagnetic metalhaving atomic number ranging from 20 to 31, 42, 43, 44, 49 and from 57to 83; f) purification by diafiltration of the aqueous solution ofcompound (XII) to remove most salts and low-molecular weight impurities,optionally preceded by a chromatographic purification step to remove thelipophilic impurities; final desalting of the aqueous solution on ionexchange resins, and g) crystallization or recovery of compound (XII).2. A process as claimed in claim 1, in which, in step a), triethylorthoformate is used in amounts ranging from 105 to 200% of thestoichiometry.
 3. A process according to claim 1, in which, in step a),the reaction temperature ranges from 110 to 150° C. and the reactiontime ranges from 5 to 24 hours.
 4. A process according to claim 1, inwhich, in step a), the acid catalyst is a carboxylic acid having atleast 3 carbon atoms.
 5. A process according to claim 1, in which, instep b), the salt of compound (IX) is selected from sodium, potassiumand calcium.
 6. A process according to claim 1, wherein thecarboxymethylation reaction of step b) is carried out between compound(III) and haloacetic acid, in molar ratios of 3 to 5 mol/mol ofhaloacetic acid to compound (III), at pH from 9.5 to 12.5 by addition ofan alkali or alkaline-earth metal hydroxide, at a temperature between 7and 50° C. for a time from 3 to 48 hours.
 7. A process as claimed inclaim 6, in which, in step b), the haloacetic acid to compound (III)molar ratio ranges from 3.2 to 4.5 and pH is from 10 to
 12. 8. A processaccording to claim 1, in which, in step c), the reaction is carried outat pH higher than 12.5, at a temperature from 65 to 100° C., for a timefrom 5 to 48 hours.
 9. A process according to claim 1, wherein thehaloacetic acid in step b) is bromoacetic acid.
 10. A process accordingto claim 1, wherein the paramagnetic metal is selected from Gd, Dy, andYb.
 11. A process according to claim 1, wherein, in step f), a 4 bedunit is used, the first bed consisting of a strongly basic anionexchanger in the hydrogen carbonate form, the second consisting of aweakly acidic cation exchanger in the H⁺ form, the third consisting of astrongly basic anion exchanger in the OH⁻ form and the fourth consistingof a weakly acidic cation exchanger in the H⁺ form.
 12. A processaccording to claim 1, wherein, in step f), resins with small sizeparticles are used.
 13. A process according to claim 1, wherein, in stepf), the strongly basic ion exchanger is selected from gel- ormacroporous- matrix resins of type I or of type II.
 14. A processaccording to claim 1, wherein, in step f), the weakly acidic ionexchanger is a gel-matrix resin.
 15. A process according to claim 1,wherein step f) comprises a chromatographic purification to remove thelipophilic impurities before the diafiltration step.
 16. A processaccording to claim 1, wherein, in formula (XII), R₁ is methyl, R₂ ishydrogen, Me³⁺ is Gd³⁺ and the epoxide of formula (XI) is propyleneoxide.
 17. A process according to claim 1, wherein, in formula (XII), R₁and R₂ are hydroxymethyl, Me³⁺ is Gd³⁺ and the epoxide of formula (XI)is 4,4-dimethyl-3,5,8-trioxabicyclo 5.1.0!octane.